4-aminobenzene-sulfone-carbamic acid derivative



Patented Nov. 26, 1946 Es PATENT-r OFF E- A 1 4-AMINOBENZENE-SULFONE-CARBAMIC 1 ACID DERIVATIVE Henry Martin, Basel, RudolfHirt,,Riehen,;and Y 7 Alfred Staub, Basel, Switzerland, assignorsltovthe firm J. R. Geigy A. G., Basel, Switzerland, acorporationof-Switzerl'and I I No Drawing. Application swim, 1945; seria1,

I No. 574,632.

It-has been found that valuable l aminobenene-sulfone-carbamiuacidderivatives are obtained-by causing sulfonamides of the aromatic seriesor their salts respectively, which contain, in 4-position, anitrogen-containing group or a substituent replaceable by such a group,to react Withdeactive' carbamic acid" derivatives and convertingeventually the 4-positioned substituent -intoan amino group;

On the other hand, it..is. also possible to cause sulfone-halides of thearomatic series containing. in' "4'-positio n,, a nitrogen-containinggroup or a substituent replaceable by such a group to react" withreactive urea derivatives such as ethers of .pseudo urea;;'t0 saponifythepseudo urea ether derivative, and to eventually convert 1 Claim. (01.2664973) In Switzerland" December- 23,

interaction of the potassium vsaltof acetyl-sulf 'anilamide. with ureaor with nitro-urea. i-acetylaminobenzene-sulfoneeurea 0 -methyl ethercan be made from. 4-acetylaminobenzene sulf0- chloride and urea-O-methylether; By means .of hydrogen halide acids the4-.acetylami-nobenzene-sulfone-urea is obtained which is converted inthe known manner into the amino compound.

All these interactions can, in the most cases,

be. carried, out directly or, ,if necessary; by .the use of solvents.or. dil'uen'ts'j, Often any. addition oi'condensation agents orcatalysts may be of importance for. an' accelerated or smooth course of'the i positi'oned substituent into an amino group;

As reactive carbamic acid derivatives, which may be used for thecondensation, especially the anhydri-des'halides, esters or amides ofcarbamic acid, are suitable, As anhydri'des of carbamic acid may beenumerated cyanic, acid or its salts, whereas as halides the carbamicacid halides -may bev employed; Asesters. the urethanesmay be used,while as amidesurea'or the ethers of its isoforin or nitro-ureaaresuitable.

As; sulfonic: acid; amides or sulfonic acid halides of thearomatic;series, which in 4-position contain a "nitrogen-containing group or asubstituent replaceable by such a, group, may be understood benzenesulfonic acid derivatives possessing in ll-position for example a freeamino group, a benzylamino group, an acylamino I group, a nitro, azo,azomethine, hydroxyl or carboxyl group or derivatives thereof or ahalogen atom.

A suitable method for the preparation of4-amino-benzene-sulfone-carbamic acid derivathe. reaction. lThusit willbeadvantageous' to work, e; g. for certainjinteractions, in the presence.of. alkalior earth.-alkali-salts or -hydroxides or of otherjsuitablesalts reacting in a basic ;manner or of, organictertiary bases,like trimethylamine, dimethylaniline, J pyridine or formylmethylaniline,etc. .7

IfYa'ccording to the above-mentioned reaction sequences. compounds areobtained which contain imp-position to. the sulfonamide group othersubstituent's than the aminogroup; for'example the benzylamino,acyla'mino, nitro, azo, azomethine' or hydroxyl' groupphalogen thecarbox'yl. group] or derivatives Ithereof or the like,

usual known methods can be applied for the formation of the free aminogroup, such'as'reduotion, saponification, exchange of hydroxyl andhalogen to the amino group, further decomposition methods according toHofmann and Curtius and the like.

4-aminobenzene-sulfone-urea is a valuable medicinal and therapeuticalsubstance against infection maladies.

The invention will now be described by Way of. r

the following examples, without being limited thereto. The parts are byWeight.

Example 1 25 parts of 4-acetylaminobenzene-sulfamide are heated underreflux for 4 to 5 hours with 15 acetylaminobenzene-sulfone-urea is partsof potassium cyanate, parts of alcohol and with 15 parts of Water. Thusthe potassium salt of the 4-acetylamino-benzene-sulfo-urea is obtained,the same being filtered oif, dissolved in dilute caustic potash lye and.saponified by a slight heating. By acidification the4-aminobenzene-sulfo-urea is precipitated. It is filtered andrecrystallised from alcohol. Melting point l 58160 C. underdecomposition.

Example 2 10 parts of 4-nitrobenzene-su1famide in 30 parts of alcoholand parts of water are heated under reflux for 8 hours with 4.5 parts ofpotassium cyanate. After cooling the potassium salt of the4-nitrobenzene-su1fo-urea is obtained, which is filtered off and reducedin acatalytical manner. The thus obtained l-aminobenzenesulfo-urea ispurified by recrystallisation from alcohol; M. P. l58-160 C. underdecomposition.

Ewample 3 24 parts of the sodium salt of acetyl-sulfanilic acid amideare suspended in 100 parts of benzene and heated to 60-65 C. Whilethoroughly stirring this mixture at the said temperature, a solution of10.5 parts of carbamic acid chloride in 20 plete.

4 Example 5 '71 parts of the sodium salt of acetyl-sulfanilamide areheated to 100 C. with 30 parts of urethane until the splitting of! ofalcohol is com- The resulting melt is dissolved in 2000 parts of waterand, after addition of 30 parts of concentrated caustic soda lye,maintained for 1 hour at 50 C. The filtered solution is neutralised withacetic acid, whereby 4-amino-benzenesulfo-urea is separated in acrystalline form. Its

melting point is l58160 C.

parts of benzene is allowed to drop thereinto.

Then the mixture is kept, while stirring for several additional hours,at 6065 C., whereupon the benzene is distilled oil. The residue isdissolved in a cold dilute caustic soda lye, then freed from anyinsoluble matters and again precipitated by acidification with aceticacid. The 4- acetylaminobenzene-sulfo-urea thus obtained is 'saponifiedby heating its solution to 50 C. in a dilute caustic soda lye and thep-aminobenzenesulfo-urea is precipitated by acidification. M. P.

158-160 C. under decomposition.

Example 4 -parts of nitrobenzene-sulfamide are susipended in 100 partsof dry dioxane. While cooling with ice, a solution of 15 parts ofpyridine in dioxane and a solution of 10 parts of carbamic "acidchloride in 10 parts of dioxane are simultaneously causedto drop intothe said suspension. Then the whole is heated to boiling for 4 hours andsubsequently the greatest part of dioxane is distilled off. The residueis poured into di-- lute hydrochloric acid, whereby the rawnitrobenzene-sulfo-urea is precipitated. By dissolvingv the same in adilute sodium carbonate solu- .tion and by filtration and subsequentacidification of the filtrate it can be recovered in a pure form ofmelting point 1989-200" C.

By catalytical hydrogenation of the nitro compound there is obtainedp-aminobenzene-sulfourea melting at 158-160 C. under decomposition.

Example 6 14 parts of urea, parts of the potassium salt ofacetyl-sulfanilamide and 16 parts of glycolmonomethyl ether are heatedto C. until any development of ammonia has ceased. The melt is powderedafter cooling, dissolved in dilute caustic soda lye, some .insolublematters are illtered off and the 4-acetylaminobenzene-sulfourea issaponified. The -aminobenzene-sulfourea is obtained from the filteredsolution by acidifying the latter. M. P. 158160 C. under decomposition.I

Example 7 being a colorless compound of excellent thera- 45 peuticproperties andhaving the melting point of 158-160 C.

HENRY MARTIN. RUDOLF HIRT.

ALFRED STAUB.

